Identification of a Potential Cardiac Antifibrotic Mechanism of Torasemide in Patients With Chronic Heart Failure
Begoña López, PhD*,
Arantxa González, PhD*,
Javier Beaumont, PhD*,
Ramón Querejeta, MD, PhD ,
Mariano Larman, MD and
Javier Díez, MD, PhD*, ,*
* Division of Cardiovascular Sciences, Centre for Applied Medical Research, University of Navarra, Pamplona, Spain
Division of Cardiology, Donostia University Hospital, San Sebastián, Spain
Division of Hemodynamics, Guipuzcoa Polyclinics, San Sebastián, Spain
Department of Cardiology and Cardiovascular Surgery, University Clinic, University of Navarra, Pamplona, Spain.
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Figure 1 Generation of Collagen Type I Fibers
Schematic representation of the steps involved in the synthesis and processing of collagen type I molecules. DNA = deoxyribonucleic acid; PCP = procollagen type I carboxy-terminal proteinase; PCPE = procollagen type I carboxy-terminal proteinase enhancer; PICP = carboxy-terminal propeptide of procollagen type I.
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Figure 2 Western Blot Autoradiograms of PCP
Representative Western blot autoradiograms of myocardial PCP from 1 patient with chronic heart failure at baseline and 8 months after randomization to furosemide (left), and 1 chronic heart failure patient at baseline and 8 months after randomization to torasemide (right). Abbreviations as in Figure 1.
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Figure 3 Western Blot Autoradiograms of PCPE
Representative Western blot autoradiograms of myocardial PCPE from 1 patient with chronic heart failure at baseline and 8 months after randomization to furosemide (left), and 1 chronic heart failure patient at baseline and 8 months after randomization to torasemide (right). Abbreviations as in Figure 1.
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Figure 4 PCP and PCPE Expression
Histological sections of myocardial biopsy specimens from 1 patient with chronic heart failure. (A, C) Immunostaining for PCP and PCPE, respectively. These molecules were identified in brown and located mostly in areas of interstitial and perivascular fibrosis (arrows). Positive staining also was seen in cardiomyocytes (arrowheads). (B, D) Negative controls for the correspondent primary antibody omission. Magnification x100. Abbreviations as in Figure 1.
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Figure 5 Association Between Aldosterone and PCP Activation
Positive correlation (y = 0.004x + 1.907) between plasma aldosterone and activation of myocardial PCP (as assessed by the ratio of PCP active form to PCP zymogen) in all patients with chronic heart failure. Abbreviations as in Figure 1.
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Figure 6 Association Between PICP and CVF
Positive correlation (y = 1.338x + 18.73) between the reduction in serum PICP and the reduction in myocardial collagen volume fraction (CVF) in patients with chronic heart failure treated with torasemide. Abbreviations as in Figure 1.
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Figure 7 Associations Among PCP Activation and CVF and PICP
(A) Positive correlation (y = 0.012x + 27.48) between the reduction in PCP activation (as assessed by the ratio of PCP active form to PCP zymogen) and the reduction in myocardial CVF in patients with chronic heart failure treated with torasemide. (B) Positive correlation (y = 0.483x + 9.979) between the reduction in PCP activation (as assessed by the ratio of PCP active form to PCP zymogen) and the reduction in serum PICP in patients with chronic HF treated with torasemide. Abbreviations as in Figure 6.
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